Heart disease continues to be the leading cause of death in the United States. The mechanism of this disease is progressive narrowing of coronary arteries by atherosclerotic plaque which can lead to acute myocardial infarction and disabling angina. One commonly used technique to change the natural history of coronary atherosclerosis is transcatheter therapy, which includes percutaneous transluminal coronary angioplasty, (or PTCA, commonly referred to as balloon angioplasty), atherectomy, and coronary stenting. During these procedures, an expandable balloon, cutting device, or metal cage mounted on a balloon, respectively, is threaded over a pre-placed wire to the site of coronary blockage. In balloon angioplasty, the balloon is inflated, compressing the atherosclerotic plaque; in atherectomy, the plaque is cut away; and in stenting, the device is expanded and deployed against the plaque. In each case, compression of the plaque and expansion of the coronary artery, or removal of the atherosclerotic plaque, restores lumen patency.
Despite the overall initial success of these procedures, approximately 20% to 50% of all patients undergoing these therapeutic procedures to clear blocked coronary arteries will suffer restenosis (re-blockage) within six months of the initial procedure. One widely accepted paradigm is that restenosis is a manifestation of the general wound healing response. The injury induced by coronary intervention causes platelet aggregation, inflammatory cell infiltration and release of growth factors, followed by smooth muscle cell proliferation and matrix formation. In this paradigm, intimal hyperplasia secondary to vascular injury is believed to be the etiology of restenosis. Numerous pharmacological agents and genes have been shown to inhibit restenosis in animal models; however, all have failed in human trials. One explanation for their failure is that suboptimal doses of agents were used in order to prevent side effects which will occur from systemic administration of the higher doses required as shown by animal studies.
The concept of localized intravascular delivery of therapeutics has become an attractive solution to overcome this limitation. Intravascular local delivery devices were recently reviewed by Hofling and Huehns [B. Hofling, T. Y. Huehns, "Intravascular Local Drug Delivery after Angioplasty," European Heart Journal 16, 437-440, 1995]. An illustration of these devices is shown in FIG. 1. The basic principles behind these delivery devices are: diffusion of drugs or genes through close contact; assisted diffusion of drugs or genes driven transmurally by pressure; and transport assisted by physical means. With these devices, successful delivery of pharmacological agents as well as genetic materials have been demonstrated in normal arteries. On the other hand, the atherosclerotic plaque remains a major barrier for this strategy of localized delivery. Delivery of a reporter gene to an atherosclerotic artery was attempted by Feldman et. al. [L. J. Feldman, P G. Steg, L. P. Zheng, "Low-Efficiency of Percutaneous Adenovirus-Mediated Arterial Gene Transfer in the Atherosclerotic Rabbit," Journal of Clinical Investigation 95, 2662-2671, 1995] Compared to normal vessels, the atherosclerotic plaque of the diseased artery behaved as a barrier and resulted in a 10 fold-reduction in transfer efficiency (0.20% vs. 2.0%, p=0.0001).
The only current method which does not rely on passive diffusion is the needle catheter shown in the right lower corner of FIG. 1. It consists of 6 needles which cut through the full thickness of the blood vessel, and deposit a gene or drug in the adventitia (outer layer) of the vessel wall. The adventitia contains the source of the blood supply to the vessel wall, which becomes the means of drug or gene delivery. However, as this catheter transects the vessel wall in an unpredictable fashion, there are serious safety concerns. In addition, since the atherosclerotic plaque will disrupt the blood supply of the coronary artery, predictable, symmetrical delivery of a drug or gene is not certain. In contrast, the present invention allows predictably diffuse delivery of a drug or gene without transection of the coronary artery. The present invention accomplishes this by using a probe of a pre-limited length, as opposed to a standard "long" needle in the needle catheter.
The present invention uses arrays of micromechanical probes which penetrate the plaque and allow for efficient transport of therapeutic agents into the artery media. The probes can be part of a coronary stent which remains in the artery, or can be part of the angioplasty balloon, which is removed after the interventional procedure. Probe height can be varied from less than 25 .mu.m to over 1000 .mu.m as required by the thickness of the compressed plaque. This invention differs from conventional methods in that a direct physical penetration of vascular plaque is accomplished. Current delivery techniques rely on diffusion of the drug through a thick layer of plaque; this diffusion is extremely slow, making the transfer ineffective for clinical purposes.
Our preferred embodiment of the invention involves a novel stent design. Stents are devices used after angioplasty to prevent elastic recoil of the compressed plaque. One type, the Palmaz-Schatz stent [Balloon-expandable Palmaz-Schatz coronary stents are manufactured by Johnson & Johnson], is shown in FIGS. 2a and 2b. FIGS. 2a and 2b show a Palmaz-Schatz coronary stent before expansion, after deployment, respectively, in a cardiac artery. The stent consists of a metal lattice, 1, with interstices, 2. First, a conventional balloon angioplasty procedure is performed to create a larger lumen in the occluded vessel. Then, using a second balloon, the stent is inflated at the site of the occlusion to a diameter slightly larger than the normal inner diameter of the vessel. The metal members comprising the stent hold the compressed plaque against the vessel wall, as shown in FIGS. 3a and 3b. FIG. 3a shows plaque build-up, 3, inside coronary artery. FIG. 3b shows after balloon angioplasty and stenting. Therapeutic agents coating the stent, 1, can pass into the vessel wall on the right side, where there is little or no plaque, but are unable to penetrate the plaque built up on the left side of the artery. The thickness of residual plaque in patients with coronary artery disease, following placement of Palmaz-Schatz stents, is generally 100 to 200 .mu.m. In order to prevent restenosis, genes or drugs placed on the surface of a stent need a means to penetrate the maximal 200 .mu.m thick layer of compressed plaque barrier to gain entry through the internal elastic lamina into the media where the smooth muscle cells reside. Therapeutic agents placed on the outside of a conventional stent can diffuse into the wall of a normal vessel, but cannot penetrate the plaque.
This problem can be overcome by fabricating the stent such that it has preferably sharp protrusions along the outer surface, FIG. 4. FIG. 4 shows probes, 5, covering the surface of the stent, 1. The probes are protrusions consisting of lateral faces, 6, and sharp tips, 7, which can pierce through the plaque. Therapeutic agents coating the probes can then diffuse into the media layer of the vessel to prevent smooth muscle cell growth and subsequent restenosis. These "probes" can pierce through the plaque, allowing therapeutic agents to find their way into the media layer of the vessel where they are needed. FIGS. 5a, b and c show the transfer of therapeutic agents is greatly enhanced by covering the surface of the stent, 1, with probes, 5. In FIG. 5a, a conventional stent compresses the plaque against the vessel wall, consisting of three layers: the intima, 8, the media, 9, and the adventitia, 10. Transfer of genes into the media depends on diffusion through the plaque, a slow and inefficient process. Texturing the surface with probes, FIG. 5b, allows the gene therapy to penetrate the plaque. In FIG. 5c, the probes are fabricated with a lumen 11, which is in communication with a reservoir.
Recently, Hashmi et. al. [S. Hashmi, P. Ling, G. Hashmi, M. L. Reed, R. Gaugler, W. Trimmer, "Genetic Transformation of Nematodes Using Arrays of Micromechanical Piercing Structures," BioTechniques 19(5), 766-770, 1995] reported the injection of DNA into nematode gonads using probes. These probes, as shown in FIG. 6, were fabricated by anisotropic wet etching of silicon in heights ranging from 10 to over 100 .mu.m. When the nematodes crawled across these probes, they created a path for therapeutics to enter their cells. Successful expression of b-galactosidase, a reporter gene that expresses a blue-green color, was seen in the progeny of the nematodes.
Similar probes have been shown to be able to penetrate both plant cells [W. Trimmer, P. Ling, C.-K. Chin, P. Orton, R. Gaugler, S. Hashmi, G. Hashmi, B. Brunett, M. L Reed, "Injection of DNA Into Plant and Animal Tissues With Micromechanical Piercing Structures," Proceedings of the Eighth International Workshop on Micro Electro Mechanical Systems (MEMS-95), Amsterdam, January 1995, pages 111-115] and blood vessel walls [M. L. Reed, H. Han, L. E. Weiss, "Silicon Micro-Velcro," Advanced Materials 4(1), 48-51, 1992][H. Han, L. E. Weiss, M. L. Reed, "Mating and Piercing Micromechanical Structures for Surface Bonding Applications," Proceedings of the Fourth IEEE Workshop on Micro Electro Mechanical Systems (MEMS-91), Nara, Japan, January 1991, pages 253-258] [R. Dizon, H. Han, A. G. Russell, M. L. Reed, "An Ion Milling Pattern Transfer Technique for Fabrication of Three-Dimensional Micromechanical Structures," IEEE Journal of Microelectromechanical Systems 2(4), 151-159, 1993] and can be used for local drug delivery. A coronary stent with a silicon carbide coating deposited using plasma-enhanced chemical vapor deposition, a common technology used to fabricate microelectromechanical systems (MEMS), has also been reported recently [M. Amon, S. Winkler, A. Dekker, A. Bolz, "Introduction of a New Coronary Stent with Enhanced Radioopacity and Hemocompatibility," Proceedings IEEE Engineering in Medicine and Biology 17, 1995].